Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT328F1L)

• DOT Name: Probable phospholipid-transporting ATPase IIA (ATP9A)
• Synonyms: EC 7.6.2.1; ATPase class II type 9A
• Gene Name: ATP9A
• Related Disease: Neurodevelopmental disorder with poor growth and behavioral abnormalities
• UniProt ID: ATP9A_HUMAN
• EC Number: 7.6.2.1
• Pfam ID: PF13246 ; PF00122 ; PF00702 ; PF16212 ; PF16209
• Sequence:
  MTDNIPLQPVRQKKRMDSRPRAGCCEWLRCCGGGEARPRTVWLGHPEKRDQRYPRNVINN
  QKYNFFTFLPGVLFNQFKYFFNLYFLLLACSQFVPEMRLGALYTYWVPLGFVLAVTVIRE
  AVEEIRCYVRDKEVNSQVYSRLTARGTVKVKSSNIQVGDLIIVEKNQRVPADMIFLRTSE
  KNGSCFLRTDQLDGETDWKLRLPVACTQRLPTAADLLQIRSYVYAEEPNIDIHNFVGTFT
  REDSDPPISESLSIENTLWAGTVVASGTVVGVVLYTGRELRSVMNTSNPRSKIGLFDLEV
  NCLTKILFGALVVVSLVMVALQHFAGRWYLQIIRFLLLFSNIIPISLRVNLDMGKIVYSW
  VIRRDSKIPGTVVRSSTIPEQLGRISYLLTDKTGTLTQNEMIFKRLHLGTVAYGLDSMDE
  VQSHIFSIYTQQSQDPPAQKGPTLTTKVRRTMSSRVHEAVKAIALCHNVTPVYESNGVTD
  QAEAEKQYEDSCRVYQASSPDEVALVQWTESVGLTLVGRDQSSMQLRTPGDQILNFTILQ
  IFPFTYESKRMGIIVRDESTGEITFYMKGADVVMAGIVQYNDWLEEECGNMAREGLRVLV
  VAKKSLAEEQYQDFEARYVQAKLSVHDRSLKVATVIESLEMEMELLCLTGVEDQLQADVR
  PTLETLRNAGIKVWMLTGDKLETATCTAKNAHLVTRNQDIHVFRLVTNRGEAHLELNAFR
  RKHDCALVISGDSLEVCLKYYEYEFMELACQCPAVVCCRCAPTQKAQIVRLLQERTGKLT
  CAVGDGGNDVSMIQESDCGVGVEGKEGKQASLAADFSITQFKHLGRLLMVHGRNSYKRSA
  ALSQFVIHRSLCISTMQAVFSSVFYFASVPLYQGFLIIGYSTIYTMFPVFSLVLDKDVKS
  EVAMLYPELYKDLLKGRPLSYKTFLIWVLISIYQGSTIMYGALLLFESEFVHIVAISFTS
  LILTELLMVALTIQTWHWLMTVAELLSLACYIASLVFLHEFIDVYFIATLSFLWKVSVIT
  LVSCLPLYVLKYLRRRFSPPSYSKLTS
• Function: Plays a role in regulating membrane trafficking of cargo proteins, namely endosome to plasma membrane recycling, probably acting through RAB5 and RAB11 activation. Also involved in endosome to trans-Golgi network retrograde transport. In complex with MON2 and DOP1B, regulates SNX3 retromer-mediated endosomal sorting of WLS, a transporter of Wnt morphogens in developing tissues. Participates in the formation of endosomal carriers that direct WLS trafficking back to Golgi, away from lysosomal degradation. Appears to be implicated in intercellular communication by negatively regulating the release of exosomes. The flippase activity towards membrane lipids and its role in membrane asymmetry remains to be proved. Required for the maintenance of neurite morphology and synaptic transmission.
• Reactome Pathway: Ion transport by P-type ATPases (R-HSA-936837)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with poor growth and behavioral abnormalities	DISP9EBZ	Strong	Autosomal recessive	[1]

10 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Probable phospholipid-transporting ATPase IIA (ATP9A).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Probable phospholipid-transporting ATPase IIA (ATP9A).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Probable phospholipid-transporting ATPase IIA (ATP9A).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Probable phospholipid-transporting ATPase IIA (ATP9A).	[5]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Probable phospholipid-transporting ATPase IIA (ATP9A).	[6]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Probable phospholipid-transporting ATPase IIA (ATP9A).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Probable phospholipid-transporting ATPase IIA (ATP9A).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Probable phospholipid-transporting ATPase IIA (ATP9A).	[10]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Probable phospholipid-transporting ATPase IIA (ATP9A).	[11]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Probable phospholipid-transporting ATPase IIA (ATP9A).	[12]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Probable phospholipid-transporting ATPase IIA (ATP9A).	[9]

References

• [1] Biallelic truncating variants in ATP9A cause a novel neurodevelopmental disorder involving postnatal microcephaly and failure to thrive. J Med Genet. 2022 Jul;59(7):662-668. doi: 10.1136/jmedgenet-2021-107843. Epub 2021 Jun 18.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Characterisation of cisplatin-induced transcriptomics responses in primary mouse hepatocytes, HepG2 cells and mouse embryonic stem cells shows conservation of regulating transcription factor networks. Mutagenesis. 2014 Jan;29(1):17-26.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [7] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [10] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [11] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [12] Alteration of estrogen-regulated gene expression in human cells induced by the agricultural and horticultural herbicide glyphosate. Hum Exp Toxicol. 2007 Sep;26(9):747-52. doi: 10.1177/0960327107083453.